tbuckley/cabot-search huggingface dataset:
Accessible Data Collections for Improved Decision Making in Neuro-Oncology Clinical Trials
Authors: Rifaquat Rahman, Steffen Ventz, Robert Redd, Timothy Cloughesy, Brian M. Alexander, Patrick Y. Wen, Lorenzo Trippa
Journal: Clinical Cancer Research (2023)

Abstract Drug development can be associated with slow timelines, particularly for rare or difficult-to-treat solid tumors such as glioblastoma. The use of external data in the design and analysis of trials has attracted significant interest because it has the potential to improve the efficiency and precision of drug development. A recurring challenge in the use of external data for clinical trials, however, is the difficulty in accessing high-quality patient-level data. Academic research groups generally do not have access to suitable datasets to effectively leverage external data for planning and analyses of new clinical trials. Given the need for resources to enable investigators to benefit from existing data assets, we have developed the Glioblastoma External (GBM-X) Data Platform which will allow investigators in neuro-oncology to leverage our data collection and obtain analyses. GBM-X strives to provide an uncomplicated process to use external data, contextualize single-arm trials, and improve inference on treatment effects early in drug development. The platform is designed to welcome interested collaborators and integrate new data into the platform, with the expectation that the data collection can continue to grow and remain updated. With such features, GBM-X is designed to help to accelerate evaluation of therapies, to grow with collaborations, and to serve as a model to improve drug discovery for rare and difficult-to-treat tumors in oncology.
Highlights From the American College of Cardiology’s 2023 Scientific Session: the Ketogenic Diet and Cardiac Events, a Wearable Sensor to Predict Troponin Levels, Bempedoic Acid for Statin Intolerance, and More
Authors: Melissa Suran
Journal: JAMA (2023)

This Medical News article discusses research presented at the American College of Cardiology and World Congress of Cardiology conference this March.
Assessment of Patient Education Delivered at Time of Hospital Discharge
Authors: Shreya P. Trivedi, Sara Corderman, Elyse Berlinberg, Antoinette Schoenthaler, Leora I. Horwitz
Journal: JAMA Internal Medicine (2023)

Importance Patient education at time of hospital discharge is critical for smooth transitions of care; however, empirical data regarding discharge communication are limited. Objective To describe whether key communication domains (medication changes, follow-up appointments, disease self-management, red flags, question solicitation, and teach-back) were addressed at the bedside on the day of hospital discharge, by whom, and for how long. Design, Setting, and Participants This quality improvement study was conducted from September 2018 through October 2019 at inpatient medicine floors in 2 urban, tertiary-care teaching hospitals and purposefully sampled patients designated as “discharge before noon.” Data analysis was performed from September 2018 to May 2020. Exposures A trained bedside observer documented all content and duration of staff communication with a single enrolled patient from 7 am until discharge. Main Outcomes and Measures Presence of the key communication domains, role of team members, and amount of time spent at the bedside. Results Discharge days for 33 patients were observed. Patients had a mean (SD) age of 63 (18) years; 14 (42%) identified as White, 15 (45%) were female, and 6 (18%) had a preferred language of Spanish. Thirty patients were discharged with at least 1 medication change. Of these patients, 8 (27%) received no verbal instruction on the change, while 16 of 30 (53%) were informed but not told the purpose of the changes. About half of the patients (15 of 31, 48%) were not told the reason for follow-up appointments, and 18 of 33 (55%) were not given instructions on posthospital disease self-management. Most patients (27 of 33, 81%) did not receive guidance on red-flag signs. While over half of the patients (19 of 33, 58%) were asked if they had any questions, only 1 patient was asked to teach back his understanding of the discharge plan. Median (IQR) total time spent with patients on the day of discharge by interns, senior residents, attending physicians, and nurses was 4.0 (0.75-6.0), 1.0 (0-2.0), 3.0 (0.5-7.0), and 22.5 (15.5-30.0) minutes, respectively. Most of the time was spent discussing logistics rather than discharge education. Conclusions and Relevance In this quality improvement study, patients infrequently received discharge education in key communication domains, potentially leaving gaps in patient knowledge. Interventions to improve the hospital discharge process should address the content, method of delivery, and transparency among team members regarding patient education.
Association Between Magnitude of Differential Blood Pressure Reduction and Secondary Stroke Prevention
Authors: Chia-Yu Hsu, Jeffrey L. Saver, Bruce Ovbiagele, Yi-Ling Wu, Chun-Yu Cheng, Meng Lee
Journal: JAMA Neurology (2023)

The degree to which more intensive blood pressure reduction is better than less intensive for secondary stroke prevention has not been delineated.To perform a standard meta-analysis and a meta-regression of randomized clinical trials to evaluate the association of magnitude of differential blood pressure reduction and recurrent stroke in patients with stroke or transient ischemic attack (TIA).PubMed, Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov were searched from January 1, 1980, to June 30, 2022.Randomized clinical trials that compared more intensive vs less intensive blood pressure lowering and recorded the outcome of recurrent stroke in patients with stroke or TIA.The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline was used for abstracting data and assessing data quality and validity. Risk ratio (RR) with 95% CI was used as a measure of the association of more intensive vs less intensive blood pressure lowering with primary and secondary outcomes. The univariate meta-regression analyses were conducted to evaluate a possible moderating effect of magnitude of differential systolic blood pressure (SBP) and diastolic blood pressure (DBP) reduction on the recurrent stroke and major cardiovascular events.The primary outcome was recurrent stroke and the lead secondary outcome was major cardiovascular events.Ten randomized clinical trials comprising 40 710 patients (13 752 women [34%]; mean age, 65 years) with stroke or TIA were included for analysis. The mean duration of follow-up was 2.8 years (range, 1-4 years). Pooled results showed that more intensive treatment compared with less intensive was associated with a reduced risk of recurrent stroke in patients with stroke or TIA (absolute risk, 8.4% vs 10.1%; RR, 0.83; 95% CI, 0.78-0.88). Meta-regression showed that the magnitude of differential SBP and DBP reduction was associated with a lower risk of recurrent stroke in patients with stroke or TIA in a log-linear fashion (SBP: regression slope, -0.06; 95% CI, -0.08 to -0.03; DBP: regression slope, -0.17; 95% CI, -0.26 to -0.08). Similar results were found in the association between differential blood pressure lowering and major cardiovascular events.More intensive blood pressure-lowering therapy might be associated with a reduced risk of recurrent stroke and major cardiovascular events. These results might support the use of more intensive blood pressure reduction for secondary prevention in patients with stroke or TIA.
Risk of Stroke, Death, and Myocardial Infarction Following Transcarotid Artery Revascularization vs Carotid Endarterectomy in Patients With Standard Surgical Risk
Authors: Patric Liang, Jack L. Cronenwett, Eric A. Secemsky, Jens Eldrup-Jorgensen, Mahmoud B. Malas, Grace J. Wang, Brian W. Nolan, Vikram S. Kashyap, Raghu L. Motaganahalli, Marc L. Schermerhorn
Journal: JAMA Neurology (2023)

Carotid artery stenting has been limited to use in patients with high surgical risk; outcomes in patients with standard surgical risk are not well known.
Functional Recovery, Symptoms, and Quality of Life 1 to 5 Years After Traumatic Brain Injury
Authors: Lindsay D. Nelson, Nancy R. Temkin, Jason Barber, Benjamin L. Brett, David O. Okonkwo, Michael A. McCrea, Joseph T. Giacino, Yelena G. Bodien, Claudia Robertson, John D. Corrigan, Ramon Diaz-Arrastia, Amy J. Markowitz, Geoffrey T. Manley
Journal: JAMA Network Open (2023)

Many level I trauma center patients experience clinical sequelae at 1 year following traumatic brain injury (TBI). Longer-term outcome data are needed to develop better monitoring and rehabilitation services.To examine functional recovery, TBI-related symptoms, and quality of life from 1 to 5 years postinjury.This cohort study enrolled trauma patients across 18 US level I trauma centers between 2014 and 2018. Eligible participants were enrolled within 24 hours of injury and followed up to 5 years postinjury. Data were analyzed January 2023.Mild TBI (mTBI), moderate-severe TBI (msTBI), or orthopedic traumatic controls (OTC).Functional independence (Glasgow Outcome Scale-Extended [GOSE] score 5 or higher), complete functional recovery (GOSE score, 8), better (ie, lower) TBI-related symptom burden (Rivermead Post Concussion Symptoms Questionnaire score of 15 or lower), and better (ie, higher) health-related quality of life (Quality of Life After Brain Injury Scale-Overall Scale score 52 or higher); mortality was analyzed as a secondary outcome.A total 1196 patients were included in analysis (mean [SD] age, 40.8 [16.9] years; 781 [65%] male; 158 [13%] Black, 965 [81%] White). mTBI and OTC groups demonstrated stable, high rates of functional independence (98% to 100% across time). While odds of independence were lower among msTBI survivors, the majority were independent at 1 year (72%), and this proportion increased over time (80% at 5 years; group × year, P = .005; independence per year: odds ratio [OR] for msTBI, 1.28; 95% CI, 1.03-1.58; OR for mTBI, 0.81; 95% CI, 0.64-1.03). For other outcomes, group differences at 1 year remained stable over time (group × year, P ≥ .44). Odds of complete functional recovery remained lower for persons with mTBI vs OTC (OR, 0.39; 95% CI, 0.28-0.56) and lower for msTBI vs mTBI (OR, 0.34; 95% CI, 0.24-0.48). Odds of better TBI-related symptom burden and quality of life were similar for both TBI subgroups and lower than OTCs. Mortality between 1 and 5 years was higher for msTBI (5.5%) than mTBI (1.5%) and OTC (0.7%; P = .02).In this cohort study, patients with previous msTBI displayed increased independence over 5 years; msTBI was also associated with increased mortality. These findings, in combination with the persistently elevated rates of unfavorable outcomes in mTBI vs controls imply that more monitoring and rehabilitation are needed for TBI.
Clinical Trials Portfolio and Regulatory History of Idelalisib in Indolent Non-Hodgkin Lymphoma
Authors: Titas Banerjee, Myung Sun Kim, Alyson Haslam, Vinay Prasad
Journal: JAMA Internal Medicine (2023)

Importance Idelalisib is a first-in-class phosphatidylinositol 3-kinase inhibitor that received US Food and Drug Administration accelerated approval in July 2014 as a single-agent treatment for relapsed follicular lymphoma (FL) and small lymphocytic lymphoma (SLL). Serious adverse effects were reported in 2016 leading to termination of postmarketing registry trials. However, idelalisib remained on the market until 2022 when Gilead voluntarily withdrew the drug for the accelerated approval indication. Objective Evaluate the regulatory oversight of the accelerated approval pathway and evidence generation for idelalisib during premarketing (2008-2014), postmarketing (2014-2016), and premarketing withdrawal periods (2016-2022). Data Sources ClinicalTrials.gov, FDA.gov, PubMed database. Study Selection Clinical trials investigating the safety and effectiveness of idelalisib. Data Extraction and Synthesis Study characteristics and relative risk (RR) of safety outcomes were abstracted. Data were pooled using random effects meta-analysis. The analysis was performed in October of 2022. Main Outcomes and Measures Trial status, recruitment status, publication status, serious adverse events (SAEs), fatal adverse events (FAEs), and all-cause mortality. Results Overall, 31 idelalisib trials met selection criteria. In total, 20 of 30 (65%) included SLL and/or FL; 13 (42%) trials were completed, 13 (42%) had published results, and 7 (23%) were randomized clinical trials (RCTs). Overall, 6 RCTs of idelalisib had publicly available data on safety outcomes. By the initial postmarketing period (2016), the cumulative RR for SAEs was 1.86 (95% CI, 1.63-2.11), for FAEs was 3.30 (95% CI, 1.56-7.00), and for death was 1.35 (95% CI, 0.85-2.12). In the premarketing withdrawal period, only a single phase 3 trial was enrolling patients for FL and was terminated. However, idelalisib was not withdrawn from the market until 2022. Gilead reported cumulative sales revenue of $842 million during market authorization (2014-2022) and annual sales had a steady decline from $168 million to $62 million during the premarketing withdrawal period (2016-2021). Conclusions and Relevance Findings of this systematic review and meta-analysis show that serious risks of SAE, FAE, and death with idelalisib treatment were evident by 2016. However, idelalisib remained on the market for another 6 years, with minimal evidence generation. It was voluntarily withdrawn for FL and SLL accelerated approval indications coinciding with decreasing revenue generation. Closer attention for safety and effectiveness of drugs reaching market by accelerated approval is needed.
Parathyroid hormone receptor-1 signaling aggravates hepatic fibrosis through upregulating cAMP response element-binding protein-like 2
Authors: Ting Hong, Xuelian Xiong, Yaqiong Chen, Qiuyu Wang, Xiao Fu, Qingnan Meng, Yan Lu, Xiaoying Li
Journal: Hepatology (2023)

Parathyroid hormone receptor-1 (PTH1R) is a class B G protein-coupled receptor central to skeletal development, bone turnover, and calcium homeostasis. However, the role of PTH1R signaling in liver fibrosis is largely unknown. Here, the role of PTH1R signaling in the activation of HSCs and hepatic fibrosis was examined.
Correction: Iceland screens, treats, or prevents multiple myeloma (iStopMM): a population-based screening study for monoclonal gammopathy of undetermined significance and randomized controlled trial of follow-up strategies
Authors: Sæmundur Rögnvaldsson, Thorvardur Jon Love, Sigrun Thorsteinsdottir, Elín Ruth Reed, Jón Þórir Óskarsson, Íris Pétursdóttir, Guðrún Ásta Sigurðardóttir, Brynjar Viðarsson, Páll Torfi Önundarson, Bjarni A. Agnarsson, Margrét Sigurðardóttir, Ingunn Þorsteinsdóttir, Ísleifur Ólafsson, Ásdís Rósa Þórðardóttir, Elías Eyþórsson, Ásbjörn Jónsson, Andri S. Björnsson, Gunnar Þór Gunnarsson, Runólfur Pálsson, Ólafur Skúli Indriðason, Gauti Kjartan Gíslason, Andri Ólafsson, Guðlaug Katrín Hákonardóttir, Manje Brinkhuis, Sara Lovísa Halldórsdóttir, Tinna Laufey Ásgeirsdóttir, Hlíf Steingrímsdóttir, Ragnar Danielsen, Inga Dröfn Wessman, Petros Kampanis, Malin Hultcrantz, Brian G. M. Durie, Stephen Harding, Ola Landgren, Sigurður Yngvi Kristinsson
Journal: Blood Cancer Journal (2023)
Systemic therapy for hormone receptor‐positive/human epidermal growth factor receptor 2‐negative early stage and metastatic breast cancer
Authors: Laura A. Huppert, Ozge Gumusay, Dame Idossa, Hope S. Rugo
Journal: CA A Cancer Journal for Clinicians (2023)

Hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer is defined by the presence of the estrogen receptor and/or the progesterone receptor and the absence of HER2 gene amplification. HR-positive/HER2-negative breast cancer accounts for 65%-70% of all breast cancers, and incidence increases with increasing age. Treatment varies by stage, and endocrine therapy is the mainstay of treatment in both early stage and late-stage disease. Combinations with cyclin-dependent kinase 4/6 inhibitors have reduced distant recurrence in the early stage setting and improved overall survival in the metastatic setting. Chemotherapy is used based on stage and tumor biology in the early stage setting and after endocrine resistance for advanced disease. New therapies, including novel endocrine agents and antibody-drug conjugates, are now changing the treatment landscape. With the availability of new treatment options, it is important to define the optimal sequence of treatment to maximize clinical benefit while minimizing toxicity. In this review, the authors first discuss the pathologic and molecular features of HR-positive/HER2-negative breast cancer and mechanisms of endocrine resistance. Then, they discuss current and emerging therapies for both early stage and metastatic HR-positive/HER2-negative breast cancer, including treatment algorithms based on current data.
<i>JAMA Pediatrics</i>—The Year in Review, 2022
Authors: Dimitri A. Christakis
Journal: JAMA Pediatrics (2023)

Last year, I began this annual review by stating "I would have hoped this year would see the end of COVID-19, but we may now be, as they say, at the end of the beginning." 1 I think it's true this time.As the COVID-19 pandemic has evolved and entered yet a new phase, so have the journal's COVID-19related submissions.Keeping up with the pace of developments has been a challenge for the journal-for any journal-as the virus and our understanding of its evolution and its implications continues.We still receive many retrospective studies telling us where the virus was or what it has done, but increasingly, now that it is clear that it will be with us for the foreseeable future (if not forever), we are receiving prospective studies.Not surprisingly, the lion's share of the journal's content pages, article views and downloads, and article citations have been for COVID-19-related articles, 2-7 but the third mostviewed article this year attempted to shed light on ongoing controversy related to early screen exposure and autism. 4Understandably, an enormous amount of scientific inquiry and editorial energy have been focused on COVID-19, but the prior priorities of pediatric health remain and we anticipate (and hope) that they will be focused on again as the pandemic continues to wane.To that end, JAMA Pediatrics remains committed to publishing research related to reducing disparities in health and promoting equity while achieving high-quality health care delivery.I want to reemphasize that we are a pediatric health journal and welcome all articles-from all disciplines-that help advance the social, cognitive, emotional, and physical health of children globally.In support of that goal, we have added a new section to our journal focusing on translational research and edited by Jason Debley, MD. 8 This section aims to help expedite our understanding of disease processes and mechanisms in ways that are accessible to a large audience.By the numbers, JAMA Pediatrics has had another extraordinary year (Table ).In 2022, our acceptance rate for original research was 6%.The denominator is a big part of that rate with more than 2600 manuscripts submitted, which presents a lot of hard work for a fantastic editorial team, Julie T. Vo and Jennifer Matte, who process manuscripts, field emails and telephone calls, and shepherd the entire process of getting submissions through the system and peer review, to editorial decisions, and scheduled for publication.
Earlier Age at Type 2 Diabetes Diagnosis Is Associated With Increased Genetic Risk of Cardiovascular Disease
Authors: Hyunsuk Lee, Jaewon Choi, Na Yeon Kim, Jong-Il Kim, Min Kyong Moon, Seunggeun Lee, Kyong Soo Park, Soo Heon Kwak
Journal: Diabetes Care (2023)

OBJECTIVE We investigated genetic risk of cardiovascular disease (CVD) by age at type 2 diabetes (T2D) diagnosis. RESEARCH DESIGN AND METHODS We compared incident CVD events by age at T2D diagnosis using UK Biobank (N = 12,321) and the Seoul National University Hospital (SNUH) cohort (N = 1,165). Genetic risk was quantified using polygenic risk score (PRS). RESULTS Individuals with earlier T2D diagnosis had higher CVD risk. In UK Biobank, the effect size of coronary artery disease (CAD) PRS on incident CAD was largest in individuals diagnosed with T2D at ages 30–39 years (hazard ratio 2.25; 95% CI 1.56–3.26) and decreased as age at diagnosis increased: ages 40–49 (1.51; 1.30–1.75), 50–59 (1.36; 1.24–1.50), and 60–69 years (1.30; 1.14–1.48) (Pinteraction = 0.0031). A similar trend was observed in the SNUH cohort. This increased genetic risk associated with earlier T2D diagnosis was largely mitigated by a healthy lifestyle. CONCLUSIONS Individuals with an earlier T2D diagnosis have a higher genetic risk of CAD, and this information could be used to tailor lifestyle interventions.
The m6A Reader YTHDF2 Promotes Bladder Cancer Progression by Suppressing RIG-I–Mediated Immune Response
Authors: Lei Zhang, Yuqing Li, Lingli Zhou, Houhong Zhou, Liefu Ye, Tong Ou, Huaishan Hong, Shiwen Zheng, Ziyu Zhou, Kang Wu, Zeqin Yan, Jean Paul Thiery, Jun Cui, Song Wu
Journal: Cancer Research (2023)

Abstract N6-Methyladenosine (m6A) is the most prevalent internal modification of mammalian mRNAs. Recent studies have shown that m6A methyltransferases METTL3 and METTL14 play important roles in urothelial bladder carcinoma (BLCA). To provide a more comprehensive understanding of the m6A regulatory landscape in bladder cancer, we investigated the role of YTHDF2, a crucial m6A reader, in BLCA. YTHDF2 was frequently upregulated at both the RNA and protein level in BLCA. Functionally, YTHDF2 promoted the proliferation and tumor growth of BLCA cells in vitro and in vivo, respectively. Integrative RNA sequencing and m6A sequencing analyses identified RIG-I as a downstream target of YTHDF2. Mechanistically, YTHDF2 bound to the coding sequence of DDX58 mRNA, which encodes RIG-I, and mediated its degradation in an m6A-dependent manner. Knockdown of RIG-I inhibited apoptosis and promoted the proliferation of BLCA cells. Depleting RIG-I was also able to reverse the effects of YTHDF2 deficiency. YTHDF2-deficient BLCA cells implanted orthotopically in recipient mice activated an innate immune response and promoted recruitment of CD8+ T lymphocytes into the tumor bed and the urothelium. Moreover, YTHDF2 deficiency enhanced the efficacy of Bacillus Calmette-Guérin immunotherapy treatment. This study reveals that YTHDF2 acts as an oncogene in BLCA. YTHDF2 inhibits RIG-I to facilitate immune evasion, supporting testing YTHDF2 inhibition in combination with immunotherapy. Significance: YTHDF2 regulates RIG-I–mediated innate immune signaling to support bladder cancer progression, highlighting the functional importance of m6A modifications in bladder cancer and uncovering therapeutic opportunities to improve patient outcomes.